Study Produces Conflicting Findings on the Use of Anti-Anemia Drug

LOS ANGELES - Results from a phase III drug trial indicate that an anti-anemia drug did not significantly decrease the need for blood transfusions in patients not on chemotherapy, and decreased overall patient survival when compared to placebo, according to researchers from the UCLA Medical Center at the 2007 Annual Meeting of the American Association for Cancer Research.

The drug, darbepoetin alfa (DA) is a synthetic form of erythropoietin, a hormone that signals the formation of new red blood cells from within the bone marrow. DA is commonly used as a means of combating anemia in cancer patients who are also receiving chemotherapy. Anemia in cancer patients can result from either chemotherapy or the cancer itself, and it has a measurable effect on quality of life and overall cancer survival.

While some cancer patients not undergoing chemotherapy are also given DA, previous placebo-controlled studies did not show that darbepoetin significantly reduced transfusion risk.

“While the study was not specifically designed to study survival rates, our results indicate a statistically significant decrease in patients given the drug versus those who were given placebo,” said John Glaspy, M.D., professor at the University of California, Los Angeles School of Medicine. “Since erythropoietic agents are sometimes used in the U. S. to treat anemia and reduce transfusion risk in patients not on chemotherapy, these results are of concern to the research and clinical cancer communities.”

The trial was designed to examine the ability of darbepoetin to reduce the need for blood transfusions in patients with active cancer not undergoing chemotherapy. The trial, held in clinical sites throughout North America, Europe and Australia was supported by the drug’s manufacturer, Amgen.

Approximately 1,000 people were enrolled in the study, which was open to patients with most forms of cancer, except myeloid or acute leukemia and Burkitt’s or lymphoblastic lymphoma. The most common cancers were non-small cell lung, breast and prostate cancer, with 82 percent of patients in disease stage III or IV.

Patients were randomly assigned to receive either DA or a placebo, and given a weekly dose until week 16 or until the patient required a blood transfusion. The patients were then given an end-of-study examination at week 19, with two years of follow up to evaluate survival. During the study, researchers monitored each patient’s hemoglobin level, an indicator of red blood cell production. Darbepoetin was withheld if the patient’s hemoglobin count exceeded 13 grams per deciliter.

According to the researchers, fewer patients in the darbepoetin group required transfusions during the study, but the overall difference between the darbepoetin and placebo groups was not statistically significant. Subsequent analysis also showed a statistically significant increase in patient deaths - during the trial and in the follow up - amid the darbepoetin arm of the trial versus the placebo group, with 136 darbepoetin patient deaths versus 94 in the placebo group. Researchers say the trial was not designed to focus on survival, prognostic factors were not balanced at baseline and no specific study procedures were undertaken to determine the exact cause of death for these patients, beyond investigator attribution.

One confounding aspect of these study results was the different reactions among patients in the darbepoetin group, says Glaspy. When treated with darbepoetin, patients with kidney, prostate, or stomach cancers, non-Hodgkin’s lymphoma, or multiple myeloma appeared to have worse survival outcomes. However, the opposite was seen among patients with breast, colon, ovarian, or cervical cancer. Indeed, many of these patients also achieved higher hemoglobin counts (yet still within the study’s safety parameters). Survival rates were also better for patients in either group who did not need to receive transfusions.

“People with cancers like myeloma and lymphoma did substantially worse than people with diseases like breast cancer, for example,” Glaspy said.

When the researchers notified Amgen of their preliminary results, the company issued a warning to doctors and informed the Food and Drug Administration as to the results of the trial. Subsequently, the manufacturer and FDA agreed to a “black box” warning for doctors about the drug’s safety in this particular circumstance. “Certainly, the first concern is about safety, although nobody wants to see an increase in transfusions among patients already on the medication and doing well,” said Glaspy.

“The findings will pose a particular puzzle to cancer researchers, as the exact mechanisms behind the observed decrease in patient survival is not clear,” Glaspy said. "Likewise, we’ll need to resolve these data in light of evidence that darbepoetin offers benefits for patients with certain types of cancer when used within chemotherapy. There are no obvious reasons for this discrepancy.